Aldose reductase is the enzyme responsible for the conversion of glucose to sorbitol in lens, sciatic nerve, retina, brain, Islets of Langerhans and other tissues. Sorbitol accumulation in diabetes mellitus and galactitol accumulation in galactosemia are implicated via an osmotic mechanism in the formation of cataracts and neuropathy. AY 22, 284, a non-toxic, orally fed aldose reductase inhibitor, was found to block sorbitol and galactitol formation in the lenses and sciatic nerves of diabetic and galactosemic rats, respectively. AY 22, 284 successfully prevented cataract formation and the motor nerve conduction velocity defect in galactosemic rats. The sorbitol pathway is also involved in the mechanism of glucose-induced insulin release, possibly as a specific glucose recognition signal. It is proposed to continue ongoing investigations (1) to study the structure of aldose reductase and characterize the active site of the enzyme; (2) into ultrastructural localization of aldose reductase and sorbitol dehydrogenase in human tissues; (3) to further develop and use a radioimmunoassay for aldose reductase in a variety of studies; (4) to define the biochemical lesions leading to increased sorbitol formation in diabetic nerve; (5) to study the effect of aldose reductase inhibitors on the metabolism of diabetic rat nerve in vivo and to use AY 22,284 to test the role of the sorbitol pathway in the formation of diabetic neuropathy; (6) to study the function of the sorbitol pathway in the mechanism of insulin release.